Hemophagocytic syndrome is a severe and often fatal syndrome resulting from excessive activation and proliferation of T lymphocytes and macrophages. Onset of a hemophagocytic syndrome characterized the course of several human inherited immune disorders, all of them resulting from molecular defects of the perforin-dependent cytotoxic process exerted by both T and Natural Killer (NK) lymphocytes. These disorders highlight the determinant role of this lytic pathway in the control of lymphocyte expansion and homeostasis. New effectors of this secretory pathway have been thus identified.